Process for preparing aminofuranes

ABSTRACT

The present invention relates to a novel method for preparing 4-aminofurans of the general formula (I) and salts thereof.

The present invention relates to a novel method for preparing 4-aminofurans of the general formula (I) and salts thereof.

4-Aminofurans of the general formula (I) (especially R¹=COOMe) are important precursors of agrochemical active ingredients (cf. WO2018/228985) and pharmaceutical active ingredients (e.g. DNA binding agents: Woods, Craig R. et al. Bioorganic & Medicinal Chemistry Letters, 12(18), 2647-2650; 2002).

4-Aminofurans of the general formula (I) serve as starting material for the preparation of tetrahydro- and dihydrofurancarboxylic acids and esters. To date, these compounds of the formula (I) have been prepared by a multi-stage synthesis including a bromination, dehalogenation, coupling reaction and deprotection. (see F. Brucoli, et al. Bioorganic & Medicinal Chemistry, 20(6), 2019-2024; 2012).

The synthesis mentioned above has a large number of disadvantages, such as low atom economy (bromination and dehalogenation), use of heavy metals such as zinc and use of protecting groups such as Boc-amine. The method described in Bioorganic & Medicinal Chemistry, 20(6), 2019-2024; 2012 furthermore requires the use of metal-containing (for example copper(I) iodide) catalysts.

These disadvantages render the method for preparing compounds of the general formula (I) uneconomic and therefore very expensive.

F. Wolter et al in (Organic Letters, 11(13), 2804-2807; 2009) describes another method for preparing aminofurans of the general formula (I), specifically via a Curtius rearrangement of dimethyl furan-2,4-dicarboxylate using (PhO₃)₂P(O)N₃. This method is unsuitable for industrial applications due to the highly explosive properties of organic azides.

Several compounds of the general formula (I), for example where R¹=CF₃ and R²=NHAryl, have been described in European Journal of Organic Chemistry 2018, 3853-3861. However, this compound was detected in a mixture of several components.

In light of the prior art described above, the object of the present invention is to find a method for preparing the compounds specified, which is cost-effective and which can be used on an industrial scale. It is also desirable to obtain these compounds with high yield and at high purity, such that they do not have to be subjected to any further complex purification.

The object described above—simple, cost-effective and large-scale production—is achieved by a method for preparing compounds of the general formula (I) and salts thereof

-   -   in which     -   R¹ is CF₃, CF₂H, C₂F₅, CF₂Cl, CCl₃, COO(C₁-C₄)alkyl, COOH,     -   R² is H, CH₃CO, CCl₃CO, CF₃CO, phenyl-CO, CH₃OCO, (CH₃)₃COCO,         phenyl, phenyl-CH₂, (diphenyl)CH,     -   characterized in that in a first step compounds of the general         formula (II)

-   -   in which     -   R³ and R⁴ are each independently H and C₁-C₄-alkyl     -   and     -   R¹ has the definitions specified above,     -   with the aid of an amine of the general formula R⁵-NH₂ (V) are         converted to compounds of the general formula (III)

-   -   in which     -   R⁵ is H, phenyl, phenyl-CH₂, (diphenyl)CH,     -   and in a second reaction step these are then reacted in the         presence of a dehydrating reagent to give compounds of the         general formula (I).

Preferred definitions of the radicals of the compounds of the general formulae (I), (II), (III), (IV) and (V) are as follows:

-   -   is CF₃, CF₂H, CF₂Cl, C₂F₅, CCl₃, COOCH₃, COOC₂H₅,     -   R² is H, CF₃CO, CH₃CO, CCl₃CO, phenyl, phenyl-CH₂, (diphenyl)CH,         CH₃OCO, (CH₃)₃COCO,     -   R³ and R⁴ are each independently H or CH₃,     -   R⁵ is H, phenyl, phenyl-CH₂, (diphenyl)CH.

Particularly preferred definitions of the radicals of the compounds of the general formulae (I), (II), (III), (IV) and (V) are as follows:

-   -   R¹ is CF₃, CF₂H, CCl₃, COOCH₃, COOC₂H₅,     -   R² is H, COCF₃, COCH₃, COCCl₃, Ph-CH₂, (diphenyl)CH, CH₃OCO,         (CH₃)₃COCO,     -   R³ and R⁴ are each independently H or CH₃,     -   R⁵ is H.

Especially preferred definitions of the radicals of the compounds of the general formulae (I), (II), (III), (IV) and (V) are as follows:

-   -   R¹ is CF₃, COOCH₃, COOC₂H₅,     -   R² is H, COCF₃, (CH₃)₃COCO,     -   R³ and R⁴ are CH₃,     -   R⁵ is H.

Further especially preferred definitions of the radicals of the compounds of the general formulae (I), (II), (III), (IV) and (V) are as follows:

-   -   R¹ is COOCH₃, COOC₂H₅,     -   R² is H,     -   R³ and R⁴ are CH₃,     -   R⁵ is H.

Further especially preferred definitions of the radicals of the compounds of the general formulae (I), (II), (III), (IV) and (V) are as follows:

-   -   R¹ is COOCH₃,     -   R² is H,     -   R³ and R⁴ are CH₃,     -   R⁵ is H.

The reaction sequence for preparing compounds of the formula (I) is shown in Scheme 2:

Scheme 2

The compounds of the formula (II) react in the first reaction step with ammonia or amines (compounds of the general formula (V)) to form compounds of the general formula (III), which are then converted in the second reaction step to compounds of the general formula (I). Several compounds of the general formula (II) and (III), in which R¹, R³, R⁴ and R⁵ have the definitions specified above, are known. These compounds can be prepared by the method known from WO 2011/073100, WO 2011/073101 and European Journal of Organic Chemistry (2018), 2018(27-28), 3853-3861.

By way of example, the following compounds of the formula (II) may be mentioned:

-   3-(2,2-dimethyl-1,3-dioxolan-4-ylidene)-1,1,1-trifluoropropan-2-one -   3-(1,3-dioxolan-4-ylidene)-1,1,1-trifluoropropan-2-one -   methyl 3-(2,2-dimethyl-1,3-dioxolan-4-ylidene)-2-oxopropanoate -   ethyl 3-(2,2-dimethyl-1,3-dioxolan-4-ylidene)-2-oxopropanoate

By way of example, the following compounds of the formula (III) may be mentioned:

-   4-amino-1,1,1-trifluoro-5-hydroxypent-3-en-2-one -   4-amino-1,1-difluoro-5-hydroxypent-3-en-2-one -   4-amino-1,1,1-trichloro-5-hydroxypent-3-en-2-one -   methyl 4-amino-5-hydroxy-2-oxopent-3-enoate -   ethyl 4-amino-5-hydroxy-2-oxopent-3-enoate -   methyl 4-benzylamino-5-hydroxy-2-oxopent-3-enoate.

In the second reaction step, the compounds of the formula (III) are cyclized. The ring closure takes place in the presence of a dehydrating reagent such as SOCl₂, POCl₃, PCl₃, phosgene, diphosgene, triphosgene, ClCOCOCl, (CF₃CO)₂, P₄O₁₀, SO₂F₂, trimethyl orthoformate and triethyl orthoformate and HCl. Preferred dehydrating reagents are SOCl₂, POCl₃, PCl₃, phosgene, diphosgene, triphosgene and ClCOCOCl. Especially preferred dehydrating reagents are SOCl₂, POCl₃, ClCOCOCl and phosgene.

Using reagents such as SOCl₂, POCl₃, PCl₃, phosgene, diphosgene, triphosgene and ClCOCOCl, compounds of the formula (I) where R²=H, CH₃, phenyl, phenyl-CH₂ and (diphenyl)CH are obtained. Said compounds are formed in the form of HCl salts thereof.

If the compounds of the general formula (I) are obtained in the form of salts thereof, for example as a hydrochloride, the salt-free forms can be obtained by treating the salt with a base, for example triethylamine (see Example 2).

Using reagents such as (CF₃CO)₂O, compounds of the formula (I) where R²=CF₃CO are obtained.

The molar ratio of the compound of the formula (III) to the cyclization reagents is in the range of about 1:0.1 to 1:5, preferably from 1:0.5 to 1:3.

Reaction step 2 is usually carried out in a temperature range of 0° C. to 40° C. and optionally in the presence of a solvent or diluent. The reaction is preferably carried out in a solvent at approximately room temperature (RT).

Preferred solvents are methanol, ethanol, isopropanol, butanol, acetonitrile, N,N-dimethylacetamide, toluene, chlorobenzene.

DESCRIPTION OF THE METHODS AND INTERMEDIATES EXAMPLES

The present invention is elucidated in more detail by the examples which follow, without restricting the invention to these examples.

Method of Measurement

The products were characterized by ¹H NMR spectroscopy and/or LC-MS (Liquid Chromatography Mass Spectrometry).

The NMR spectra were determined using a Bruker Avance 400 fitted with a flow probe head (volume 60 μl). In individual cases, the NMR spectra were measured with a Bruker Avance II 600.

Example 1

Methyl 4-aminofuran-2-carboxylate hydrochloride (salt of the formula (I)

15.9 g (0.1 mol) of methyl 4-amino-5-hydroxy-2-oxopent-3-enoate were suspended in 50 ml of methanol and the mixture was cooled to 0° C. 17.7 g (0.15 mol) of SOCl₂ were added thereto at 0° C. over 2 hours. The mixture was stirred at 10° C. for a further 5 hours and the precipitate was filtered off, washed with 5 ml of methanol and dried. This gave 16.8 g, 95% of pale beige crystals.

¹H-NMR (400 MHz, CDCl₃): δ 10.07 (3H, s, br.); 8.10 (1H, d); 7.32 (1H, d); 3.83 (3H, s) ppm.

¹³C-NMR 158.0 (s); 143.6 (s); 140.2 (d); 121.8 (s); 114.5 (d); 52.3 (q) ppm.

Example 2

Conversion of methyl 4-aminofuran-2-carboxylate hydrochloride (salt of the formula (I)) to methyl 4-aminofuran-2-carboxylate (salt-free product of the formula (I))

9.2 g of methyl 4-aminofuran-2-carboxylate hydrochloride were suspended in 50 ml of ethyl acetate and 15.7 g of Et₃N were added. The mixture was stirred at RT for 3 hours, the precipitate was filtered off and ethyl acetate fully concentrated under vacuum. This gave 6.96 g, 95% of beige crystals, with m.p. 79-81° C.

¹H-NMR (400 MHz, CDCl₃): δ: 7.24 (1H, d); 6.8 (1H, d); 4.3 (2H, s) 3.75 (3H, s) ppm.

Example 3 Methyl 4-[(2,2,2-trifluoroacetyl)amino]furan-2-carboxylate

1.59 g (0.01 mol) of methyl 4-amino-5-hydroxy-2-oxopent-3-enoate were suspended in 50 ml of dichloromethane and the mixture was cooled to 0° C. 2 ml of (CF₃CO)₂O were added thereto at 0° C. over 2 hours. The mixture was stirred at 10° C. for a further 5 hours and 20 ml of water were added. The mixture was stirred for 5 h at room temperature (RT) and then the phases were separated. The organic phase was concentrated. The precipitate was stirred with 5 ml of diisopropyl ether and filtered off. This gave 1 mg of the product as a beige solid.

¹H-NMR (400 MHz, CDCl₃): δ 11.76 (1H, s, br.); 8.26 (1H, d); 7.24 (1H, d); 3.76 (3H, s) ppm.

¹³C-NMR 158.2 (s); 154.1 (s, q); 142.5 (s); 137.4 (d); 124.7 (s); 115.8 (s); 112.1 (d); 52.3 (q) ppm. 

1. A method for preparing a compound of formula (I) and/or salt thereof,

in which R¹ is CF₃, CF₂H, C₂F₅, CF₂Cl, CCl₃, COO(C₁-C₄)alkyl, COOH, R² is H, CH₃CO, CCl₃CO, CF₃CO, phenyl-CO, CH₃OCO, (CH₃)₃COCO, phenyl, phenyl-CH₂, (diphenyl)CH, Comprising converting a compound of formula (II)

in which R³ and R⁴ are each independently H and C₁-C₄-alkyl and R¹ has the definitions specified above, with aid of an amine of formula R⁵-NH₂ (V) to a compound of formula (III)

in which R⁵ is H, phenyl, phenyl-CH₂, (diphenyl)CH, and then reacting said compound of formula III in presence of a dehydrating reagent to give a compound of formula (I).
 2. The method according to claim 1, wherein definitions of radicals of compounds of formulae (I), (II), (III), (IV) and (V) are as follows: R¹ is CF₃, CF₂H, CF₂Cl, C₂F₅, CCl₃, COOCH₃, COOC₂H₅, R² is H, CF₃CO, CH₃CO, CCl₃CO, phenyl, phenyl-CH₂, (diphenyl)CH, CH₃OCO, (CH₃)₃COCO, R³ and R⁴ are each independently H or CH₃, R⁵ is H, phenyl, phenyl-CH₂, (diphenyl)CH.
 3. The method according to claim 1, wherein definitions of radicals of compounds of formulae (I), (II), (III), (IV) and (V) are as follows: R¹ is CF₃, CF₂H, CCl₃, COOCH₃, COOC₂H₅, R² is H, COCF₃, COCH₃, COCCl₃, phenyl-CH₂, (diphenyl)CH, CH₃OCO, (CH₃)₃COCO, R³ and R⁴ are each independently H or CH₃, R⁵ is H.
 4. The method according to claim 1, wherein definitions of radicals of compounds of formulae (I), (II), (III), (IV) and (V) are as follows: R¹ is CF₃, COOCH₃, COOC₂H₅, R² is H, COCF₃, (CH₃)₃COCO, R³ and R⁴ are CH₃ R⁵ is H.
 5. The method according to claim 1, wherein definitions of radicals of compounds of formulae (I), (II), (III), (IV) and (V) are as follows: R¹ is COOCH₃, COOC₂H₅, R² is H, R³ and R⁴ are CH₃, R⁵ is H.
 6. The method according to claim 1, wherein definitions of radicals of compounds of formulae (I), (II), (III), (IV) and (V) are as follows: R¹ is COOCH₃, R² is H, R³ and R⁴ are CH₃, R⁵ is H.
 7. The method according to claim 1, wherein the reaction is carried out at room temperature.
 8. The method according to claim 1, wherein the solvent is methanol, ethanol, isopropanol, butanol, acetonitrile, N,N-dimethylacetamide, toluene or chlorobenzene.
 9. The method according to claim 1, wherein the dehydrating reagent is SOCl₂, POCl₃, PCl₃, phosgene, diphosgene, triphosgene, ClCOCOCl, (CF₃CO)₂, P₄O₁₀, SO₂F₂, trimethyl orthoformate and triethyl orthoformate or HCl.
 10. The method according to claim 1, wherein the dehydrating reagent is SOCl₂, POCl₃, PCl₃, phosgene, diphosgene, triphosgene or ClCOCOCl.
 11. The method according to claim 1, wherein the dehydrating reagent is SOCl₂, POCl₃, ClCOCOCl or phosgene. 